Azetidine-2-carboxylic acid is an unusual amino acid, the (S)-enantiomer of which is known to be useful in the synthesis of inter alia high molecular weight polypeptides and in particular as an analogue of the well known amino acid proline.
This amino acid is of limited availability from natural sources and consequently the development of an efficient and economic synthetic method for its production is desirable.
That 4-amino-2-halobutyric acids may be cyclised under basic conditions to form azetidine-2-carboxylic acid has been known for many years. For example, Fowden (in Biochem. J. (1956) 64, 323) employed barium hydroxide and Duplan et al (in Bull. Soc. Chem. Chim. France (1968) 4079) employed sodium hydroxide to effect the conversion.
The person skilled in the art would anticipate that in order to maximise the efficiency of intermolecular cyclisation to form the strained four-membered ring, the reaction should be carried out at low concentrations. At higher concentrations it would be expected that the prevalence of competing reactions, such as intramolecular displacement of the bromine atom to form dimers, oligomers or polymers, would significantly decrease efficiency. Indeed, the above authors report only low concentrations (e.g. 10 to 15 g/L) of halo- (in this case bromo-) amino acid; the use of higher concentrations is not suggested.
It will also be appreciated by those skilled in the art that concentrations of the magnitude reported in the above-mentioned prior art are of little practical utility in large scale industrial synthesis. Typical problems which are encountered include poor vessel utilisation, higher effluent output and increased difficulty in product isolation, all of which can render a process economically unviable.
Surprisingly, we have found that the aforementioned cyclisation may be carried out cleanly and efficiently at concentrations which are high enough to be of practical utility in an industrial process.